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Journal of the American Chemical Society
Koten and J. G. Noltes, J. Chem. SOC., Chem. Commun., 575 (1974); J. Organomt. Chem.. 84, 419 (1975); G. van Koten. A. J. Leusink, and J. G. Noltes, ibid., 84, 117 (1975); G. van Koten and J. G. Noltes, ibid., 84, 129 (1975). (28) T. Cohen and I. Cristea, J. Am. Chem. SOC.,98,748 (1976): J. Org. Chem., 40, 3649 (1975). (29) G. van Koten and J. G. Noltes, J. Chem, SOC.,Chem. Commun., 59 (1972). (30) A. S.Kende. L. S.Liebeskind, C. Kubiak, and R. Eisenberg, J. Am. Chem. SOC., 98, 6389 (1976). (31) We are indebted to Professor A. T. Sneden, Virginia Commonwealth University, for this sample. (32) W. C. Kofron and L. M. Baclawski, J. Org. Chem., 41, 1879 (1976). (33) J. Attenburrow, A. F. B. Cameron, J. G. Chapman, R. M. Evans, B. A. Hems, A. B. A. Jansen, and T. Walker, J. Chem. SOC.,1094 (1952). (34) M. Harfenist, A. Bavley, and W. A. Lazier, J. Org. Chem., 19, 1608 (1954). (35) John Anthony Schwartz. Ph.D. Thesis, Yale University, 1977. (36) C. D. Gutsche. E. F. Jason, R. S.Coffey, and H. E. Johnson, J. Am. Chem.
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January 16, 1980
SOC.,80, 5756 (1958). (37) R. Pschorr, Justus Liebigs Ann. Chem.. 391, 23 (1912). (38) H. M. Fales, E. W. Warnhoff, and W. L. Wildman, J. Am. Chem. Soc., 77, 5885 (1955). (39) K.Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon. J. Chem. SOC.,39 (1946). (40) Y . Nishizawa. Bull. Chem. SOC.Jpn., 34, 1170 (1961). (41) Some of the copper reagents precipitate at this point. Homogeneity is achieved during warming of the reaction mixture. (42) Hydrolysis with aqueous HOAc/CH&Ig has been found to be superior to mineral acid hydrolysis. See the Experimental Section, compound 28b. (43) T. Ikeda. W. I. Taylor, Y. Tsuda, S.Uyeo, and H. Yahima, J. Chem. SOC., 4749 (1956). (44) I. R. C. Bick, J. Harley-Mason, N. Sheppard, and M. J. Verengo. J. Chem. SOC.,1896 (1961). (45) M. Hanaoka, H. Sussa, C. Shimezawa, and Y. Arata. Chem. Pharm. Bull., 1216 (1974). (46) Y. Naya and M. Kotake, Nippon Kagaku Zasshi, 86, 313 (1965). (47) E. J. Corey and J. W. Suggs, Tetrahedron Lett., 2647 (1975).
Synthesis of Chartreusin Aglycone T. Ross Kelly,*’ Joseph A. Magee, and Franz R. Weibel Contributionfrom the Department of Chemistry, Boston College, Chestnut Hill,Massachusetts 021 67. Receiced June 18, 1979
Abstract: A short regiospecific synthesis of chartreusin aglycone (2) is described. Diels-Alder addition of 4 and 5 under oxidizing conditions affords benzanthracenedione 6. Reductive methylation of 6 gives 7 (90%), which is oxidatively cleaved to diacid 8 (54%). Treatment of 8 with HBr/HOAc provides 2 (64%).
The antibiotic chartreusin (1)* was first fully characterized by Schmid et al.,in 1960.334Although the antibacterial properties of 1 failed to attract lasting attention, recent findings that chartreusin exhibits pronounced activity in a number of anticancer screenss led to a resurgence of interest in the pharmaceutical applications of this structurally unique molecule. To date no synthesis of either l or its aglycone 2 has appeared. W e now report a short, regiospecific preparation of 2. The general strategy was based on the perception that 2 might be available by oxidative cleavage of an appropriately
9
Scheme I
0
6
4
5
0 1
1 m,
FH3
2
t@ c\
OOH OCH3 + @ c\ CH30
CH3
7
8
1, R= fucose-digitalose
3
zene, I04-/KMn04) failed, but the more circumspect approach employing successive oxidations with OsO4/ NaC103,12,13C r 0 3 , and H2O2I4gives 8 in 54% overall yield via 9 and 10. Treatment of 8 with refluxing HBr/HOAc3 for
2, R=H
substituted benzanthracene as shown in 3. The synthesis is outlined in Scheme I. Thus Diels-Alder reaction between 21 g of juglone (4) and 33 g of s6 in refluxing toluene for 1 week under oxidizing conditions (chloranil plus 0 2 atmosphere) following the procedure of Manning et al.738affords 14.5 g of 6 regiospecifically. There is no evidence to indicate that any of the alternative regioisomer is produced. The assignment of regiochemistry to 6 was initially based on the known regiochemical propensities of juglone9 and styrenesI0 in their Diels-Alder reactions with unsymmetrical partners;’ I the eventual obtention of 2 affirms this assignment. Reductive methylation of ‘6 (Na2S204, KzC03, and (CH3)2S04 in refluxing acetone) provides 7 (90%).Attempts to effect conversion of 7 to 8 in a single step ( 0 3purple , ben0002-7863/80/ I502-0798$01.OO/O
CH3b
bH
9
CH&
0
10
16 h followed by workup in hot aqueous acid3 affords 2 (64%), identical with an authentic sample.
Experimental Section Melting points were determined in Pyrex capillaries and are uncorrected. N M R spectra were recorded on a Hitachi Perkin-Elmer Model R-24 spectrometer in CDCI3; chemical shifts are reported in 0 1980 American Chemical Society
/ Synthesis of Chartreusin Aglycone
799
parts per million downfield from internal Me&. IR and UV-vis spectra were recorded on Perkin-Elmer spectrometer Models 421 and 575, respectively. Chromatographies were performed on either Merck silica gel 60 (230-400 mesh) or neutral, activity I alumina (80-200 mesh, Fisher Scientific). Analyses were performed by Galbraith Laboratories, Knoxville, Tenn. 1 1-Hydroxy-1-methoxy-4-methylbenz[ a]anthracene-7,12-dione (6).A solution of 21 .O g of juglone (4)and 60.0 g of chloranil in 300 mL of toluene was heated to reflux in a I-L round-bottom flask. A solution of 33.0 g of 5-methoxy-2-methylstyrene (5)6in 300 mL of toluene was added and the solution was refluxed for 6 days under an 0 2 atmosphere. The mixture was then cooled to room temperature, filtered, washed with 2 X 500 mL of 10% NaHSO3 (to remove residual 4). dried over Na2S04, filtered twice, and evaporated to dryness. Filtration through 200 g of silica gel using CH2C12 as eluent and chromatography on 350 g of alumina using 50:l CH2C12/AcOH yielded 14.5 g (37%) of pure 6.Recrystallization from EtOH/CH2C12 gave an analytical sample as brown crystals: mp 181-182 "C; N M R 6 2.51 (3 H, s), 3.85 (3 H, s), 6.6-7.6 (5 H, m), 8.01 (2 H, s), 11.65 (1 H, s). Anal. Calcd for C20H1404: C, 75.46; H, 4.43. Found: C, 75.37; H, 4.44. 4-MethyI-1,7,11,12-tetramethoxybenz[a]anthracene (7).A suspension of 1.01 g of adduct 6, 15 g of K2C83, and 10 mL of dimethyl sulfate in 100 mL of acetone was heated at reflux under an N2 atmosphere. After 3 h 1.O g of Na2S204 was added, and the stirred suspension was refluxed for 20 h. After cooling, 100 mL of water with I O mL of 1 N N a O H was added. After 2 h the solution was concentrated, extracted with CH2C12, and dried over MgS04. Chromatography on alumina using CH2Cl2 as eluent yielded 1 .OO g (90%) of pure 7 as a yellow solid: mp 46 "C dec; N M R 6 2.65 (3 H , s), 3.40 (3 H, s), 3.97 (3 H, s), 4.05 (6 H, s), 6.9-8.1 (7 H, m). Molecular ion calcd for C23H2204: 362.1518. Found: 362.1528. 4-Methyl-1,7,11,12-tetramethoxybenz[a]anthracene-5,6-dione(IO). Solutions of 498 mg of compound 7 in 20 mL of T H F and 146 mg of NaCIO3 in 20 mL of water were mixed. After the addition of 6 mg of O s 0 4 , the mixture was stirred for 75 h at 50 'C. After cooling to 25 "C, 5 mL of a 10% NaHSO3 solution in water was added. After 1 h the mixture was extracted with ether (3 X 100 mL). The organic extracts were combined, dried over Na2S04, and evaporated to dryness, yielding 525 mg of crude p r o d ~ c t .The ' ~ crude material was dissolved in 20 mL of pyridine and a solution of 520 mg of C r 0 3 in 10 mL of pyridine was added. After stirring for 18 h, the mixture was extracted with 2 X 100 mL of ether. The ether extracts were washed with 1.5 N HCI until all pyridine was removed, dried over Na2S04, and evaporated to dryness. Chromatography on silica gel using ether as eluent yielded 358 mg of diketone 10 (65%). An analytically pure sample was obtained as brown crystals by recrystallization from EtOH: mp 187-188 "C; N M R 6 2.65 (3 H, s), 3.50 (3 H, s), 3.98 (3 H , s), 4.07 (3 H , s), 4.25 (3 H, s), 7.0-8.1 ( 5 H, m). Anal. Calcd for C23H2006: C, 70.40; H, 5.14. Found: C, 70.13; H , 5.26. 3-(2-Carboxy-6-methoxy-3-methylphenyl)1,4,5-trimethoxy-2naphthoic Acid (8).A solution of 20 mL of THF, 5 mL of H202 (30%), and 128 mg of diketone 10 was prepared and allowed to stand for 24 h. After this period, 5 mL of 1 N NaOH was added slowly and carefully (very exothermic), and the solution was stirred for 4 h at room temperature. The solution was then acidified with 1.5 N HCI and extracted with ether. The ether extract was dried over Na2S04 and evaporated to give a solid which was recrystallized twice from ethyl acetate/heptane, yielding I15 mg (83%) of diacid 8 as colorless crystals, mp 208-209 "C. A mixture of synthetic 8 with naturally derived3 8 [mp 207-209 "C (lit.3 208-209 "C)] melted at 207-209 "C; N M R (both samples) 6 2.30 (3 H, s), 3.45 (3 H, s), 3.60 (3 H, s), 4.05 (3 H, s), 6.85-7.9 ( 5 H, m), 9.45 (2 H , bs, exchanges with D20). Chartreusin Aglycone (2).A solution of 58 mg of diacid 8 in 30 mL of AcOH saturated with HBr was heated at reflux for 24 h under N2. The mixture was evaporated to dryness; 30 mL of I N HCI was added and the mixture was stirred under reflux for 18 h . Evaporation to
dryness and sublimation of the crude product at 265 "C (0.1 Torr) yielded 29.3 mg (64%) of pure aglycone as chartreuse needles, mp 31 1-312 "C. AmixtureofsyntheticZandauthentic2 [mp309-310 "C (lit. 310-31 l,3b315-316 oC3a)]meltedat 309-310 "C. Aglycone 2 was insufficiently soluble to obtain an N M R spectrum. The IR and UV spectra of synthetic and authentic 2 are superimposable and in agreement with published3 data.
Kelly, Magee, Weibel
Acknowledgments. We thank Professor M. Hesse and Mr. H. Kuhne (Universitat Zurich) for making available samples of 2 and its dimethyl ether prepared in the laboratories of the late Professor Schmid and also Dr. J. Berger (Hoffmann-La Roche)2 for samples of 1 and 2. We also thank Drs. J. Douros and M. Suffness of the National Cancer Institute for providing the biological data,5 Professor L. Vining4 (Dalhousie University) and Dr. W. B. Manning7," for helpful information, and Dr. H. Dali for preliminary studies. Support of the National Cancer Institute (CA-1763 1) is gratefully acknowledged. We thank Dr. C. E. Costello of the Mass Spectrometry Facility at Massachusetts Institute of Technology (supported by PHS Grant RR-003 17) for recording high-resolution mass spectra. References and Notes Recipient of NIH Career Development Award (CA-00040), 1975-1980. Leach, B. E.; Calhoun, K. M.; Johnson, L. E.; Teeters, C. M.; Jackson, W. G. J. Am. Chem. Soc.1953, 75,4011.Berger. J.; Sternbach, L. H.; Pollock, R . G.; La Sala, E. R.; Kaiser, S.; Goldberg, M. W. /bid. 1958, 80, 1636. (a) Simonitsch, E.; Eisenhuth, W.; Stamm, 0. A. Helv. Chim. Acta 1960, 43, 58;1964, 47, 1459.Eisenhuth, W.; Stamm, 0. A,; Schmid, H. /bid. 1964,47, 1475.(b) For other studies on the structure of 1 see: Sternbach, L. H.; Kaiser, S.; Goldberg, M. W. J. Am. Chem. SOC. 1958, 80, 1639. For biosynthetic studies which suggest that 2 arises from oxidative cleavage of a benzopyrene and emerges via an intermediate akin to 8, see: Canham. P. ; Vining. L. C.; Mclnnes, A. G.; Walter, J. A.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1976,319. For an account of some of this work see: McGovern, J. P.; Neil, G. L.; Crampton, S. L.; Robinson, M. I.;Douros, J. D. Cancer Res. 1977,37, 1666. T/C's against B-16 melanoma and P-388and L-1210leukemia in mice are 277,231,and 166,respectively; the chemotherapeutic potential of 1 is seriously compromised by its rapid excretion through the bile (personal communications from Drs. J. Douros and M. Suffness, NCI). Whether this limitation can be overcome with analogues is presently unknown, but is under investigation in other laboratories (cf. Beisler, J. A,; Takai, M.; Vehara, Y. "Abstracts of Papers", 178th National Mesting of the American Chemical Society, Washington, D.C., Sept 1979; American Chemical Society: Washington, D.C., 1979;MEDi 47). Kelly, T. R.; Dali, H. M.; Tsang, W.-G. Tetrahedron Lett. 1977,3859. Manning, W. B.; Tomaszewski, J. E.; Muschik, G. M.; Sato, R. I. J. Org. Chem. 1977, 42, 3465.See also ref 11. For Diels-Alder-based synthesis of benzanthraquinones employing 1,4phenanthraquinone as the dienophile see: Rosen. 6. I.;Weber, W. P. J. Org. Chem. 1977,42, 3463.Harvey, R. G.; Fu, P. P.; Cortez. C.; Pataki, J. Tetrahedron Lett. 1977,3533.Wunderly, s. W.; Weber, W. P. J. Org. Chem. 1978, 43, 2277. See: Kelly, T. R.: Montury, M. TetrahedronLen. 1978,4311. and references cited therein. Onishchenko, A. S. "Diene Synthesis"; Israel Program for Scientific Translations: Jerusalem, 1964;Chapter V. After the regiospecific preparation of 6 had been achieved, Manning and colleagues reported that the Diels-Alder reaction between juglone and styrene itself gives a 2:1 mixture of regioisomers; the major regioisomer has a structure consistent with the structure assigned to 6: Manning, W. B.; Muschik, G. M.; Tomaszewski, J. E. J. Org. Chem. 1979, 44, 699. Manning, W. B. Tetrahedron Lett. 1979, 1661. Cook, J. W.; Schoental, R. J. Chem. SOC.1948, 170.Badger, G. M.; Lynn, K. R. /bid. 1950, 1726. Wiesner, K.; Chan, K. K.; Demerson, C. Tetrahedron Lett. 1966, 5939. Buchi, G.; Demole, E.; Thomas, A. J. Org. Chem. 1973, 38, 123. Kyburz, E.; Riniker. B.; Schenk, H. R.: Heusser, H.; Jeger. 0. Helv. Chim. Acta 1953, 36, 1891. In a similar experiment this mixture was separated by silica gel chromatography using 4:l CH2CI2/Et2O1yielding 38% of diol 9 and 20% of diketone IO. An analytically pure sample of diol 9 was obtained as colorless crystals by recrystallization from EtOH/CH2CI2:mp 205 OC; NMR 6 2.45 (3H,s),2.65(1 H,bs,D20exchanges),3.40(3H,s),3.85(3H,s),4.0(6 H.s), 5.05(2H.bs), 6.35(1H. bs, D20exchanges),6.9-7.8(5H,m).Anal. Calcd for C23H2406: C, 69.68;H, 6.10.Found: C. 69.56;H, 6.14.
